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A novel 4-gene prognostic signature for hypermutated colorectal cancer

Authors Ge W, Cai W, Bai R, Hu W, Wu D, Zheng S, Hu H

Received 24 October 2018

Accepted for publication 1 February 2019

Published 4 March 2019 Volume 2019:11 Pages 1985—1996

DOI https://doi.org/10.2147/CMAR.S190963

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 2

Editor who approved publication: Dr Chien-Feng Li


Weiting Ge,1 Wen Cai,1,2 Rui Bai,1 Wangxiong Hu,1 Dehao Wu,1,2 Shu Zheng,1 Hanguang Hu1,2

1Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; 2Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Background: Hypermutated colorectal cancer (CRC) reportedly accounts for 15%–17% of all cases of CRC. However, the proportion and number of patients with hypermutated CRC cannot be unappreciated. Additionally, therapy options for these patients differ from those for CRC patients, with a greater potential benefit from immunotherapy.
Materials and methods: We sequenced the tumor mucosa of CRC patients with >24 months of follow-up data at our center and identified mutation profiles of hypermutated CRC as a training data set (Zhejiang University [ZJU]); we then collected patients from The Cancer Genome Atlas (TCGA) as a validation data set. Recurrently mutated genes were combined to calculate a compound score via Cox proportional hazards model. Patients with higher-than-median scores were segregated as the high-risk group. Outcomes were analyzed by Kaplan–Meier and Cox regression analyses using Python (3.6.0) and R (3.4.0).
Results: We constructed a 4-gene signature (ACVR2A, APC, DOCK2, and POLE), with training in 45 hypermutated patients at ZJU and validation in 24 hypermutated patients from TCGA. Patients in the high-risk group showed poor survival (adjusted HR =9.85, 95% CI: 2.07–46.81, P=0.004). Further subgroup analysis was performed for stage II and III colon cancer (HR =10.91, 95% CI: 1.36–87.5, P=0.005) and high microsatellite instability (MSI-H) CRC (HR =12.57, 95% CI: 1.57–100.69, P=0.002) subgroups, which verified that our signature is universal. We then compared our prognostic signature with other risk factors (including MSI status, POLE driver mutation, BRAF-p.V600E, tumor mutational burden, and TNM staging). The results proved that our 4-gene signature is better than the other risk factor for prognosis in hypermutated CRC.
Conclusion: Our 4-gene signature is a good predictor of survival for hypermutated CRC, and this signature is powerful in stage II and III colon cancer and MSI-H CRC. Future prospective studies are needed to confirm the power of the 4-gene signature in patients receiving immunotherapy.

Keywords: colorectal cancer, hypermutation, gene signature, prognosis



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